Study to Investigate the Safety and Clinical Activity of GSK3326595 and Other Agents to Treat Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukaemia (AML)
Trial Status: Active
GSK3326595 is a potent, selective, reversible inhibitor of the protein arginine methyltransferase 5 (PRMT5) / Methylosome protein 50 (MEP50) complex that is being tested as an oral treatment for human subjects with cancer. Myelodysplastic syndrome and acute myeloid leukaemia are bone marrow neoplasms for which novel, effective therapies are desperately needed. This is an open-label, multicentre, multi-part study to evaluate the safety, tolerability, and clinical activity of GSK3326595 in subjects with relapsed and refractory MDS, chronic myelomonocytic leukaemia (CMML), and hypoproliferative AML that has evolved from an antecedent MDS. The study will be conducted in two parts and at the end of Part 1, if pre-specified criteria are met, then the study will be expanded with three additional parts that will be opened in parallel (Part 2A, 2B and 2C). Part 1 is composed of a single-arm dose expansion cohort to determine the clinical benefit rate of GSK3326595. Part 2A is a randomized head-to-head Phase II evaluation of GSK3326595 compared to investigator's choice of best available care (BAC). Part 2B is composed of an abbreviated series of dose escalation cohorts followed by a single-arm dose expansion cohort to determine the overall response rate of the combination of GSK3326595 plus 5-azaciditine in newly-diagnosed MDS. Part 2C is a single-arm dose expansion study to evaluate the clinical activity of single-agent GSK3326595 in subjects with AML whose disease contains mutations in spliceosome proteins.
- Males and females ≥18 years of age (at the time consent is obtained).
- Capable of giving signed informed consent.
- Able to swallow, retain, and absorb orally-administered medication.
- Eastern cooperative oncology group (ECOG) performance status of 0, 1, or 2.
- Diagnosis of one of the following: Part 1: MDS classified as intermediate, high, or very high risk by International Prognostic Scoring System-Revised [IPSS-R] criteria, or Chronic myelomonocytic leukaemia (CMML) classified as intermediate-2 or high risk per CMML-specific prognostic scoring system (CPSS) or clinical/molecular CPSS (CPSS-mol) criteria, or MDS/CMML secondary to prior anti-neoplastic therapy, of any risk score, or AML, which has evolved from an antecedent MDS/Myeloproliferative neoplasms (MPN) of any risk score, provided that the myeloblast percentage in the marrow is ≤ 30% or the peripheral white blood cell count is less than 20,000 cells/microliter (μL) in the absence of leukoreducing therapy (e.g., hydroxyurea, leukapheresis) NOTE: Subjects without a documented history of antecedent MDS/MPN must have AML with myelodysplasia-related changes or recurrent cytogenetic abnormalities per World Health Organization (WHO) criteria Part 2A: MDS classified as intermediate, high, or very high risk by IPSS-R criteria, or CMML classified as intermediate-2 or high risk per CPSS or CPSS-mol criteria, or MDS/CMML secondary to prior anti-neoplastic therapy, of any risk score, or AML, which has evolved from an antecedent MDS/MPN of any risk score, provided that the myeloblast percentage in the marrow is ≤ 30% or the peripheral white blood cell count is less than 20,000 cells/μL in the absence of leukoreducing therapy (e.g., hydroxyurea, leukapheresis). Subjects without a documented history of antecedent MDS/MPN must have AML with myelodysplasia-related changes or recurrent cytogenetic abnormalities per WHO criteria Part 2B: MDS classified as high/very high by IPSS-R criteria, or CMML classified as intermediate-2 or high risk per CPSS or CPSS-mol criteria, or MDS/CMML secondary to prior anti-neoplastic therapy, of any risk score Part 2C: AML (irrespective of antecedent MDS and myeloblast percentage in the marrow, irrespective of hydroxyurea therapy)
- Prior therapy Part 1: Subjects must have disease that failed to respond to, or progressed despite, treatment at least one systemic therapy Part 2A: Subjects must have disease that failed to respond to, or progressed despite, treatment with at least one systemic therapy Part 2B: Subjects must have received no prior therapy for their disease, or have completed no more than one cycle of a hypomethylating agent Part 2C: Subjects must have disease that has failed to respond to, or progressed despite treatment with, at least one but no more than four prior lines of systemic therapy
- Molecular markers Part 1: At least 12 subjects must have documented loss-of-function mutation(s) at least one of the following genes/proteins: Splicing factor 3B subunit 1 (SF3B1), Serine and arginine rich splicing factor 2 (SRSF2), U2 Small Nuclear RNA Auxiliary Factor 1 (U2AF1), or Zinc Finger CCCH-Type, RNA Binding Motif and Serine/Arginine Rich 2 (ZRSR2); in addition, at least 12 subjects must have documented wild type status of all of these genes/proteins. While enrolment will initially proceed without consideration of mutational status, enrolment may be limited to one group or the other as the study proceeds based on the enrolment rates in each group, in order to ensure this minimum number of mutated and wild type subjects. Part 2A: No specific mutational or molecular requirements Part 2B: No specific mutational or molecular requirements Part 2C: Subjects must have a documented loss-of-function mutation(s) at least one of the following genes/proteins: SF3B1, SRSF2, U2AF1, or ZRSR2
- Subjects with a prior history of stem cell transplant (autologous and/or allogeneic) are allowed if: At least 3 months has elapsed from the time of transplant and the subject has recovered from transplant-associated toxicities prior to the first dose of GSK3326595 and For subjects with a prior history of allogeneic transplant, the subject has been off systemic immunosuppressive medications (including but not limited to: cyclosporine, tacrolimus, mycophenolate mofetil, or corticosteroids) for at least 1 month prior to the first dose of GSK3326595. Topical steroids are permitted; there are no signs or symptoms of acute graft versus host disease, other than Grade 1 skin involvement; there are no signs or symptoms of chronic graft versus host disease requiring systemic therapy.
- All prior treatment-related toxicities must be National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4 ≤ Grade 1 (except alopecia [permissible at any Grade] and peripheral neuropathy [which must be ≤ Grade 2]) at the time of treatment allocation. Subjects with treatment-related toxicities that are unlikely to resolve per the investigator may be enrolled on a case-by-case basis after discussion with the medical monitor
- Adequate organ system functions (at both screening and where applicable pre first Dose are defined as follows: For hematologic: Platelets laboratory values were >=10 X 10^9/Liter (subjects may receive transfusion to ensure adequate platelet counts); Prothromin time (PT)/ International normalized ratio (INR) and Partial Thromboplastin Time (PTT) laboratory values were <=1.5 X upper limit of normal (ULN), unless subject is receiving systemic anticoagulation; For hepatic: Albumin laboratory values were >=2 grams per deciliter (g/dL); Total bilirubin laboratory values were <=1.5 x ULN. NOTE: Isolated bilirubin >1.5 X ULN is acceptable if: bilirubin is fractionated and direct bilirubin <35% OR subject has a diagnosis of Gilbert's syndrome Alanine aminotransferase (ALT) laboratory values were <=2.5 x ULN; For Renal: Estimated glomerular filtration rate (eGFR)a laboratory value was >=60 mL/min/1.73m2 (a= EGFR should be calculated using the Chronic Kidney Disease Epidemiology Collaborative (CKD-Epi) method:- Females, serum creatinine >62 μmol/L: 144 x (serum creatinine x 0.0113/0.7)−1.209 x 0.993age; Females, serum creatinine <=62 μmol/L: 144 x (serum creatinine x 0.0113/0.7)−0.329 x 0.993age; Males, serum creatinine >80 μmol/L: 141 x (serum creatinine x 0.0113/0.9)−1.209 x 0.993age; Males, serum creatinine ≤80 μmol/L: 141 x (serum creatinine x 0.0113/0.9)−0.411 x 0.993age); For Cardiac: Ejection fraction >=Lower limit of normal (LLN) by echocardiogram (minimum of 50%) Troponin (I or T) <= ULN. In situations where laboratory results are outside the permitted range, the investigator may opt to retest the subject and the subsequent within range screening result may be used to confirm eligibility.
- Agree to abide by the gender-specific contraceptive requirements
- History of prior solid organ transplant
- History of a second malignancy, excluding non-melanoma skin cell cancer, within the last three years Subjects with second malignancies that were indolent, in situ or definitively treated may be enrolled even if less than three years have elapsed since treatment. Subjects with a recent history of ductal carcinoma in situ (DCIS) that has been definitively treated may be enrolled irrespective of the time since diagnosis. Consult the GSK Medical Monitor if second malignancies meet the requirements specified above.
- Active severe or uncontrolled infection. Controlled infections are permitted.
- Symptomatic or untreated Central Nervous System (CNS) disease Note that lumbar puncture (LP) is not required for study enrollment unless there is clinical suspicion for CNS disease Subjects with a history of CNS disease are permitted to enroll if they have previously received appropriate therapy and CNS remission has been documented. Subjects on maintenance intrathecal chemotherapy may be enrolled and continue to receive therapy.
- Recent prior therapy, defined as follows: Any non-monoclonal anti-cancer therapy within 14 days or 5 half-lives, whichever is longer, prior to the first dose of Investigational product (IP). Subjects in cohort 2B may enroll during the first cycle of 5-azacitidine and continue cycle 1 in combination with IP, after discussion between the investigator and the medical monitor. Prior therapy with biologic agents (including monoclonal antibodies) within 28 days prior to the first dose of IP. Any radiotherapy within 14 days or major surgery within 28 days prior to the first dose of IP. Note: subjects receiving hormonal therapy for a definitively-treated malignancy (e.g., adjuvant therapy of localized breast or prostate cancer) may continue to receive adjuvant therapy during study, after discussion with the medical monitor
- Prior therapy with any Protein arginine methyltransferase 5 (PRMT5) inhibitor
- Current use of a prohibited medication or planned use of any forbidden medications during treatment with study drug(s)
- History of known human immunodeficiency virus (HIV) infection, or positive HIV test result at screening.
- Presence of hepatitis B surface antigen (HBsAg) or positive hepatitis C antibody test result at screening. NOTE: Subjects with positive Hepatitis C antibody due to prior resolved disease can be enrolled only if a confirmatory negative Hepatitis C RNA polymerase chain reaction (PCR) (or comparable test) is obtained.
- Any of the following cardiac abnormalities: History, within the past 6 months prior to first dose of study drug(s), of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting Baseline Corrected QT (Fridericia's formula) interval (QTcF) ≥480 msec. Uncontrolled arrhythmias. Subjects with rate-controlled atrial fibrillation prior to first dose of study drug(s) may be eligible. Class II, III or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system.
- History of sensitivity to any of the study medications, or components thereof, or a history of drug or other allergy that, in the opinion of the investigator or Medical Monitor, contraindicates their participation.
University of Alabama at Birmingham Cancer Center
Contact: Kimo Bachiashvili
University of Miami Miller School of Medicine-Sylvester Cancer Center
Beth Israel Deaconess Medical Center
Massachusetts General Hospital Cancer Center
M D Anderson Cancer Center
Trial Phase Phase I
Trial Type Treatment
- Primary ID 208809
- Secondary IDs NCI-2019-02959
- Clinicaltrials.gov ID NCT03614728